Lindin Inger, Wuxiuer Yimingjiang, Kufareva Irina, Abagyan Ruben, Moens Ugo, Sylte Ingebrigt, Ravna Aina Westrheim
Medical Pharmacology and Toxicology, Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, Tromsø No-9037, Norway.
Theor Biol Med Model. 2013 Sep 14;10:56. doi: 10.1186/1742-4682-10-56.
Mitogen-activated protein kinase-activated protein kinase 5 (MK5) is involved in one of the major signaling pathways in cells, the mitogen-activated protein kinase pathway. MK5 was discovered in 1998 by the groups of Houng Ni and Ligou New, and was found to be highly conserved throughout the vertebrates. Studies, both in vivo and in vitro, have shown that it is implicated in tumor suppression as well as tumor promotion, embryogenesis, anxiety, locomotion, cell motility and cell cycle regulation.
In order to obtain a molecular model of MK5 that can be used as a working tool for development of chemical probes, three MK5 models were constructed and refined based on three different known crystal structures of the closely related MKs; MK2 [PDB: 2OZA and PDB: 3M2W] and MK3 [PDB: 3FHR]. The main purpose of the present MK5 molecular modeling study was to identify the best suited template for making a MK5 model. The ability of the generated models to effectively discriminate between known inhibitors and decoys was analyzed using receiver operating characteristic (ROC) curves.
According to the ROC curve analyzes, the refined model based on 3FHR was most effective in discrimination between known inhibitors and decoys.
The 3FHR-based MK5 model may serve as a working tool for development of chemical probes using computer aided drug design. The biological function of MK5 still remains elusive, but its role as a possible drug target may be elucidated in the near future.
丝裂原活化蛋白激酶激活的蛋白激酶5（MK5）参与细胞中的主要信号通路之一，即丝裂原活化蛋白激酶通路。MK5于1998年由洪倪和李沟新的团队发现，并被发现在整个脊椎动物中高度保守。体内和体外研究均表明，它与肿瘤抑制、肿瘤促进、胚胎发生、焦虑、运动、细胞迁移和细胞周期调控有关。
为了获得可作为化学探针开发工作工具的MK5分子模型，基于密切相关的丝裂原活化蛋白激酶（MKs）的三种不同已知晶体结构构建并优化了三种MK5模型；MK2 [蛋白质数据库（PDB）：2OZA和PDB：3M2W]以及MK3 [PDB：3FHR]。本MK5分子建模研究的主要目的是确定最适合构建MK5模型的模板。使用受试者工作特征（ROC）曲线分析生成模型有效区分已知抑制剂和诱饵的能力。
根据ROC曲线分析，基于3FHR优化的模型在区分已知抑制剂和诱饵方面最有效。
基于3FHR的MK5模型可作为使用计算机辅助药物设计开发化学探针的工作工具。MK5的生物学功能仍然难以捉摸，但其作为潜在药物靶点的作用可能在不久的将来得到阐明。
